Palatable orally administered liquid medicaments for relief of discomfort and flavoring combinations therefor

ABSTRACT

A liquid composition for the relief of discomfort, in particular, premenstrual and menstrual discomfort including, as active pharmaceutical agents, an effective amount of one or more of an analgesic, an antihistamine and a diuretic, the active agents being dissolved in a liquid vehicle, the composition containing 5-25 percent by volume alcohol and being flavored with an active flavoring composition including (1) citrus and mint ingredients, (2) vanilla and mint ingredients, or (3) citrus, vanilla and mint ingredients, the active flavoring ingredients being present in an amount sufficient to mask the unpleasant taste of the pharmaceutically active agents.

This application is continuation of application Ser. No. 07/693,725,filed Apr. 30, 1991 now abandoned, which was a continuation-in-part ofapplication Ser. No. 07/523,036, filed May 8, 1990 now U.S. Pat. No.5,011,688, which was a continuation-in-part of application, Ser. No.07/309,078, filed Feb. 2, 1989, now abandoned, which application was acontinuation of application Ser. No. 07/074,548, filed Jul. 17, 1987,now abandoned.

This invention relates broadly to a liquid composition for the relief ofdiscomfort, in particular premenstrual and menstrual discomforts anddysmenorrhea. More specifically, it relates to a liquid medicinecomprising one or more active pharmaceutical agents, e.g., an analgesic,an antihistamine, or a diuretic, in combination with unique combinationsof flavoring ingredients which effectively mask the unpleasant taste ofthe active pharmaceutical agents.

BACKGROUND OF THE INVENTION

Premenstrual syndrome (PMS) is the term in common use to describe thecomplex of physical and mental symptoms which occur from seven tofourteen days prior to the onset of the menstrual flow. Menstrualdiscomforts include primary dysmenorrhea which includes painfulmenstruation and cramping.

Menstruation occurs in women from the age of twelve to thirteen yearsto, on the average, forty-seven years of age. It occurs at more or lessregular intervals, except during pregnancy and lactation. The normalmenstrual cycle averages twenty-eight days with some variation based onthe woman's age, physical and emotional well being, and other factors.The duration of menstrual flow is variable but usually between three andseven days.

The symptoms of premenstrual syndrome are varied and may range from mildto incapacitating. As many as seventy to ninety percent of allmenstruating women have recurrent premenstrual symptoms and as many astwenty to forty percent suffer some degree of temporary mental orphysical incapacitation. The psychological symptoms includeirritability, lethargy, depression, anxiety, sleep disorders, cryingspells, and hostility. The neurological symptoms include headaches,dizziness, fainting, and seizures. Among the physical symptoms aretenderness and swelling in the breasts, constipation, abdominal bloatingand cramping, edema in the extremities, less frequent urination, andacne.

The physical, neurological, and psychological symptoms of premenstrualsyndrome and dysmenorrhea are a major cause of discomfort to women, andcause substantial loss of time and efficiency in the workplace. The arthas attempted to address these problems in a number of nonprescriptionpharmacological compositions for the treatment of premenstrual andmenstrual discomforts without completely successful results.

Most nonprescription products contain either aspirin or acetaminophen asthe analgesic. Aspirin and acetaminophen are believed to have equivalentanalgesic efficacy for the diminution of headache and other minor pains.Their relative efficacy for relieving premenstrual and menstrual painhas not been determined. Nevertheless, both agents are routinely usedfor diminishing menstrual pain. Another analgesic frequently recommendedis ibuprofen.

Most nonprescription products also contain an antihistamine such aspyrilamine maleate. They also contain diuretics in an amount which wouldbe subtherapeutic if taken separately. The most frequently useddiuretics are ammonium chloride, caffeine, and pamabrom.

Among the compositions available to provide relief from one or more ofthe symptoms of premenstrual syndrome and menstrual discomforts are thecommercial products Midol, Midol PMS, Pamprin, and Premensyn PMS. Midolhas been marketed as an aspirin tablet containing caffeine and anantispasmodic ingredient. Midol is currently marketed containingacetaminophen and pyrilamine maleate. Midol PMS, Premensyn PMS, andPamprin all contain acetaminophen, a diuretic, and an antihistamine. Allof these active ingredients are considered safe and effective incombination.

Although the commercially available compositions are useful to relievesymptoms of premenstrual syndrome and menstrual discomforts, none arecompletely effective. Liquid compositions would be desirable because aliquid vehicle speeds the action of both the analgesic and the diureticand potentiates the active ingredients. Moreover, many persons havedifficulty swallowing medications in solid form.

The problem facing the art, however, is that liquids containinganalgesic, antihistamine, and diuretic active pharmaceutical agentstaste terrible and pharmaceutical chemists have heretofore failed tosatisfactorily mask the bitter principals and aftertaste. No patentableliquid products containing this combination of actives are available inthe market.

The solid compositions now on the market for relief of premenstrual andmenstrual discomfort, including uncoated and chewable tablets, typicallytaste bitter and metallic. It has always been a difficult challenge forthe pharmaceutical chemist in compounding over-the-counter medicines tomask the bitter, metallic, and otherwise unpleasant tastes and lingeringaftertastes of many active pharmaceutical agents. This is a particularproblem when a liquid dosage form is desirable because in liquid dosageforms the bad taste is usually more apparent than in solid dosage formsincluding uncoated tablets. It is recognized among pharmaceuticalchemists and physicians that patients' compliance with a dosage scheduleis of paramount importance for controlling the symptoms and accordinglythe organoleptic properties of any medicine must be such that thepatient's resistance to following a schedule of administration isminimized.

Among the worst tasting active pharmaceutical agents in over-the-countermedicines, and particularly medicinal liquids, are analgesics,antihistamines, antitussives, sedatives, and others. When these agentsare used in combination with one another, the problem is exacerbated. Anumber of products have failed in the marketplace when patients haverefused to take repeat doses even though the active pharmaceuticalingredients were effective for the intended purpose.

Among the ingredients used by pharmaceutical chemists to mask thebitterness of the active pharmaceutical agents are licorice, anise,anethol, glycerrhizins such as ammonium glycyrrhizin, etc., vanillin,ethyl vanillin, methyl salicylate, and menthol and other mild surfaceanesthetics. The purpose of these flavoring enhancing ingredients is tointeract with the bitter principals of the active pharmaceutical agentsand to deceive the taste receptors in the mouth. These ingredients havetypically fallen short of masking the taste of active pharmaceuticalagents, particularly those with strong bitter aftertastes. Theseaftertastes remain in the mouth long after the initial impact of themedicine which may have been successfully masked.

OBJECTS OF THE INVENTION

It is a primary object of the invention to provide a liquidpharmaceutical composition designed for the relief of a broad spectrumof discomforts, particularly those associated with premenstrualsyndrome.

It is still a further object of this invention to provide apharmaceutical unit dose in liquid form desirably for nighttimeadministration, but for daytime use as well, which delivers an effectiveamount of an analgesic, an antihistamine, and/or diuretic to a patient.

It is still a further object of this invention to provide apharmaceutical dose in liquid form, of an effective composition forrelief of symptoms of premenstrual and menstrual discomforts whichtastes pleasant and which contains flavor ingredients which mask thebitter principals of the active pharmaceutical agents and deceive thetaste receptors in the mouth.

THE INVENTION

In its broadest embodiment, the invention is in a liquid composition forthe relief of discomfort comprising, as active pharmaceutical agents, aneffective amount of one or more of an analgesic, an antihistamine, and adiuretic, said active agents being unpleasant in taste and dissolved ina liquid vehicle, said composition containing 5-25 percent by volumealcohol and being flavored with an active flavoring compositioncontaining flavor enhancing ingredients comprising (a) citrus and mintingredients, or (b) vanilla and mint ingredients, or (c) citrus, vanillaand mint ingredients, said active flavoring ingredients being present inan amount sufficient to mask the unpleasant taste of thepharmaceutically active agents.

The objects of the invention are achieved in a preferred liquidcomposition for the relief of premenstrual syndrome which comprises, asactive pharmaceutical agents, an analgesic, an antihistamine, and adiuretic. These active ingredients are dissolved in a liquid vehiclewhich contains alcohol in from 5 to 25 percent by volume and preferablyfrom 12 to 25 percent by volume of the total composition. The liquidcomposition is flavored with active flavoring elements selected from thegroup consisting of citrus, vanilla, and mint, the active elements beingpresent in an amount sufficient to mask the unpleasant taste of thepharmaceutically active agents.

In the preferred embodiments of the invention, the active pharmaceuticalagents are acetaminophen as the analgesic, pyrilamine maleate as theantihistamine, and pamabrom as the diuretic. The liquid compositions ofthe invention contain a citrus flavoring ingredient in from 0.02 to 0.31percent by weight of the composition. The vanilla flavoring is presentin from 0.05 to 1.5 percent by weight of the composition. The mintflavoring ingredient is present in an amount sufficient to mask thetaste of the pharmaceutically active agents but in an amount of from0.02 to 0.16 percent by weight, the lower amount being sufficient toneutralize the flavor receptors in most regions of the mouth andconsequently allow the passage of the unpleasant principals withoutdetection, and the higher amount being still less than that amount whichwould be detected by the subject. Desirably the liquid compositions alsocontain at least 30 percent corn syrup or other sweetening syrups.

Suitable compositions and dosages of the active agents are well known inthe art and have been approved by the Food and Drug Administration. Theyare described in the Federal Register, "DEPARTMENT OF HEALTH AND HUMANSERVICES, Food and Drug Administration, 21 CFR Part 357 (Docket No.82N-0165), Orally Administered Menstrual Drug Products forOver-the-Counter Human Use; Establishment of a Monograph, Agency: Foodand Drug Administration; Action: Advance notice of proposedrulemaking."--the "Monograph", Volume 47, No. 235, Tuesday, Dec. 2,1982, at 55076-55101.

With respect to dosage, a preferred composition will comprise a oneounce dose to be taken four times per day, thereby providing the maximumdaily dosage per the Monograph. Other compositions may provide the samemaximum daily dosage in one-half to two ounce doses, again in accordancewith "Monograph".

With respect to the flavorings, the citrus flavors are included fortheir bridging characteristics, pleasant top notes, high volatility, andgood initial coverage. The vanilla flavoring ingredients, e.g.,butterscotch, are included for their good volatility, their ability tobe blended with bitter notes, their intermediate duration, and theirexcellent smoothing of incompatible metallic notes. The mints areincluded for their mild and temporary anesthetic action, i.e., they maskthe bitter notes of the active pharmaceutical agents, particularly theantihistamines, but they are not perceived by most subjects. It iscritical to the invention that the several groups be employed in properbalance.

The combination of flavoring components is critical to the compositionand to its utility as a pharmaceutical product intended for regularconsumption. The critical combination of such flavor enhancingcomponents was determined after substantial empirical, trial and errorresearch. While reference to the pharmaceutical literature was made,significant departures from the standard recommendations of thatliterature were made in making the invention.

It was understood that the intended product containing the three activeingredients described above would be compounded in a pharmaceuticalvehicle containing corn syrup and alcohol. It was realized that the taskof masking the offensive flavors of the three medicaments would beextremely difficult but it was also recognized that unless those flavorscould be masked, women would not repeatedly consume the compositionsevery four weeks or so and the product would have no practical value.

As a first step, it was noted that acetaminophen displays bitter, acridand sour notes which cannot be covered by sweetening agents; thatpyrilamine maleate is bitter but that it also has a strong, lingeringmetallic aftertaste, not unlike the taste of copper salts; and thatPamabrom is sour, quite salty and bitter. Moreover, it was recognizedthat even at very low concentrations, substantially lower than theintended dosage, the combination of actives displays an even moreintense and longer lasting acrid bitterness than do the individualcomponents. This amplified intensity and longer lasting acrid bitternessmay be explained by the fact that bitter and acidic taste receptors arelocated on the upper surface at the tip of the tongue, thereby enhancingthe sensitivity to the impact of these taste notes.

Reference was then made to the pharmaceutical literature. The referencesconsulted included: L. Lachman, H. Lieberman and J. Kanig, The theory ofPraxis of Industrial Pharmacy, 2d Edition, 1976, Lea & Febiger,Philadelphia, Pa.; Remington's Pharmaceutical Sciences, 15th Edition,1975, Mack Publishing Co, Easton, Pa.; Flavor Research and FoodAcceptance, Arthur D. Little, 1958, Reinhold Publishing Co., N.Y.; andpublished and unpublished flavoring guides distributed by severalfragrance and flavor suppliers.

Lachman et al, pages 541-566, recommends a series of masking flavors,including wild cherry, walnut, chocolate, passion fruit, mint, spice andanise. These and other similar flavors were obtained from flavorsuppliers and incorporated in the test compositions. Several of thesewere given to a taste panel consisting of twelve women of ages 16 to 45.All of the compositions tested were unanimously and emphaticallyrejected by the panelists. Thus it was found that for this particularlyintensely distasteful mixture of active components, departures had to bemade from the recommendations of Lachman et al.

Reference was then made to Remington, page 1227 et. seq., which suggestsan even larger number of flavoring agents in addition to those mentionedin Lachman et al. These encompass nearly all of the commonly usedflavoring agents. Experiments were carried out with flavoredcompositions containing cocoa syrup, raspberry, cinnamon, orange syrup,licorice syrup and aromatic elixir. Again, the panel rejected all of theflavored compositions as being unacceptably distasteful. Nevertheless,some satisfaction was expressed by some panelists with respect tocompositions containing the citrus, which apparently covered some of thetaste of the acidic and sour/salty tasting active ingredients.

Based on this preliminary lead, the inventors pursued the citrus flavor(orange) by combining it with lemon oils to further enhance the topnotes and improve the overall volatility of the flavor blend. Since thetests indicated that citrus flavors alone would not mask all of theintense and disagreeable flavors of the three-component mixture ofactive ingredients, further tests were carried out with furtherflavoring components which would serve as masking agents of bitterprincipals. The masking agents which were included in furtherexperimental compositions included: ammoniated glycyrrhizin (a licoricederivative), Veltol, a proprietary vanillin compound (Pfizer) andMagnasweet, another proprietary vanillin-based composition (FoodMaterials). The panelists reacted somewhat more positively to thecompositions containing both enhanced citrus flavors and thevanillin-based masking flavors.

The essentially two-component flavoring mixture was then subjected tofurther experimentation. In particular, ethylvanillin was compoundedwith caramel-type flavors to produce a pronounced butterscotch effectand this blend was added to the orange-lemon flavors using differentratios. The panelists confirmed a definite improvement and noted thatthe bitterness of the composition was substantially masked. However, thelingering metallic aftertaste due to the pyrilamine maleate, was stillrecognized by a majority of the panel members and it was clear thatfurther efforts would be necessary to obtain a flavoring compositionwhich would satisfactorily mask the worst flavors of the activeingredients.

In a next series of experiments, it was determined that the way toovercome the bitterness of the pyrilamine maleate was to include in thecomposition a mild surface anesthetic for the flavor receptors. Menthol,a common flavoring additive for that purpose, was attempted but even atextremely low concentrations it proved to be incompatible with the otherconstituents. The flavor combinations produced an unacceptable and oddflavor mix.

Mint oils were then tested for their efficacy as mild surfaceanesthetics for the flavor receptors. After considerable testing it wasfound that mint flavorings, when employed at concentrations below thatat which they were detectable as an individual flavor component, i.e.,at subliminal concentrations, nevertheless served as an excellent maskof the metallic aftertaste of the composition.

Compositions containing the active ingredient, corn syrup, alcohol, andthe three flavors described, were again given to the panel forevaluation. The result was unanimous approval by the panelists. In orderto investigate how the consumer would react to repetitive use of theproduct, the panelists were given repeated doses for three to five daysof normal use, each panelist receiving a sufficient supply of thecomposition with an instruction to consume one full dose (one ounce)daily before bedtime for a period of five days. The panelists reportedthat the product was satisfactory.

An additional test was repeated with 51 additional subjects. In total,63 subjects consumed the test compositions. The results of these testsare summarized in the following table:

    ______________________________________                                                     Good to Excellent                                                                         Fair    Poor                                         ______________________________________                                        overall taste impression                                                                     88.9%          7.9%    3.2%                                    mouthfeel      96.8          1.6     1.6                                      sweetness      100.0         --      --                                       absence of unpleasant                                                                        85.7          7.9     6.4                                      ______________________________________                                        aftertaste                                                                    ______________________________________                                    

While the foregoing portions of the specification are directed to thepreferred embodiments of the invention, it has been found thatsignificant benefits are achieved in masking the bitter flavors ofactive pharmaceutical ingredients using an active flavoring composition[i.e. a flavor enhancing composition] comprising (a) citrus and mintingredients, or (b) vanilla and mint ingredients, or preferably (c)citrus, vanilla and mint ingredients. The liquid compositions of theinvention are otherwise substantially the same as described above, theactive flavoring ingredients being present in an amount sufficient tomask the unpleasant taste of the pharmaceutically active agents and themint flavoring ingredient being present in an amount below the tastethreshold for mint of the ultimate subject.

The novel two ingredient compositions or three ingredient compositionscan be used to mask the unpleasant taste of a single activepharmaceutical agent, e.g. ibuprofen or acetaminophen or pyrilaminemaleate or diphenhydramine or pamabrom and may be used to mask thebitter taste of combinations of those active ingredients, e.g. activeagents comprising ibuprofen and pyrilamine maleate and pamabrom.

Preferred Compositions

The preferred compositions and concentrations of the several flavoringredients are set forth below. All percentages are by weight of theindividual flavoring ingredient.

    ______________________________________                                                         (% by Wt.)                                                                              (% by Wt)                                          Component        Range     Preferred                                          ______________________________________                                        (A)  citrus:                                                                  (1)  orange: oil of Valencia                                                       orange, terpeneless                                                                              20-50   30-40                                              citral             5-20     8-12                                              geraniol           2-5     2.5-4.0                                            d-limonene         1-10    2.5-6.5                                            geraniol acetate   1-3     1.5-2.0                                            rhodinal         0.5-2     0.7-1.2                                            linalool         0.2-2     0.5-1.2                                            linalyl acetate  1.5-6     2.5-4                                              ethyl alcohol    q.s.                                                                          (quantity                                                                     sufficient)                                             (2)  lemon:                                                                        oil of lime, terpeneless                                                                         3-15    5-8                                                citral             2-10    3-6                                                geraniol           0.1-0.5 0.2-0.4                                            aldehyde C8      0.1-1     0.3-0.7                                            aldehyde C12     0.1-1     0.3-0.7                                            nerol            0.1-1     0.2-1.2                                            rhodinal           0.1-2.0 0.2-1.2                                            oil of lemon, terpeneless                                                                        1-10    2-6                                                geraniol acetate   1-3     1.5-2.5                                            d-limonene       0.1-2     0.2-1.2                                            linalool           0.1- 2.5                                                                              0.3-1.8                                            benzyl butyrate    2-10    3-6                                                ethyl alcohol    q.s.                                                    (B)  vanilla-butterscotch                                                          ethyl maltol       1-6     2-5                                                vanillin           1-10    2-6                                                ethyl vanillin   0.1-5     0.2-1.5                                            heliotropin      0.1-5     0.2-1.5                                            cyclotene        0.1-4     0.3-1.5                                            propyleneglycol  q.s.                                                         ethyl butyrate     1-8     2-5                                                diacetyl ketone    1-8     2-5                                           (C)  mint                                                                          peppermint oil, Chinese,                                                                        0.5-10   1.5-3.5                                            specially fractionated                                                        spearmint oil    0.1-5     0.5-2.0                                            1-menthol          10-60   35-50                                              1-menthone       0.1-2     0.2-1.5                                            1-carvone        0.1-3     0.4-2                                              cineole          0.1-2     0.2-1                                              isomenthone      0.1-1     0.2-0.5                                            1-limonene       0.1-2     0.2-1.5                                            ethyl alcohol    q.s.                                                    ______________________________________                                    

The citrus ingredients are desirably present in from 0.02 to 0.31percent of the total liquid composition. The vanilla flavoringingredient is desirably present in from 0.05 to 1.5 percent of the totalcomposition, and the mint flavoring is present in a subliminal amount,i.e., an amount greater than that necessary to mask the unpleasant tasteof the active pharmaceutical agents but less than the taste thresholdfor mint of the ultimate subject. The mint ingredient is preferablycontained in an amount from 0.02 to 0.16 percent by weight of the totalliquid composition.

The citrus ingredient preferably comprises 0.05 to 0.20 percent oforange ingredient and from 0.05 to 0.16 percent by weight of lemoningredient. Still better results are obtained where the orangeingredient is present in from 0.07 to 0.12 percent by weight and thelemon ingredient is present in from 0.03 to 0.14 percent by weight ofthe liquid composition.

The following examples are representative of the compositions of theinvention and the methods which may be employed to prepare liquidcompositions according to the invention.

EXAMPLE I

A liquid mixture is prepared having the following composition.

    ______________________________________                                        Component     Label Claim Overage  Gms/Liter                                  ______________________________________                                        (1) ethyl alcohol 95%,                                                                          25% v/v     2%     218.7                                        USP           (100% ethanol)                                                  propyleneglycol,                 72.5                                         USP                                                                           acetaminophen,                                                                              1000 mgs/fl. oz                                                                           2%     34.6                                         USP                                                                           methylparaben                    1.0                                          propylparaben                    0.15                                     (2) demin. water                     102.4                                        pyrilamine maleate,                                                                          30 mgs/fl. oz                                                                            2%     1.04                                         USP                                                                           citric acid, anh,                1.50                                         USP                                                                       (3) demin. water                     102.4                                        pamabrom       50 mgs/fl. oz                                                                            2%     1.73                                     (4) high fructose corn               599.73                                       syrup (sp. gr. 1.321)                                                     (5) flavors:                                                                      natural and artificial           0.99                                         orange                                                                        natural and artificial           1.15                                         lemon                                                                         natural and artificial           0.69                                         mint                                                                          natural and artificial           3.39                                         butterscotch                                                                  sodium saccharin                 1.80                                     (6) color solutions                  1.76                                                                          1,145.53                                 ______________________________________                                    

The foregoing composition is made according to the following method. Thealcohol and propylene glycol are added to a first stainless steel mixingvessel equipped with a stainless steel agitator and explosion-proofmotor. The alcohol and propyleneglycol are agitated and theacetaminophen, methylparaben, and propylparaben are added. Agitation iscontinued until a clear solution is obtained. Demineralized water andpyrilamine maleate are added to a second stainless steel mixing vesseland agitated until the pyrilamine maleate is dissolved. The aqueoussolution of pyrilamine is then added to the solution of acetaminophenand pamabroms in the solution in the first mixing vessel. Demineralizedwater and pamabrom are then mixed in the second vessel until thepamabrom is dissolved and that solution is also added to the mixture inthe first vessel. Corn syrup is added to the first vessel and themixture is agitated taking care that no crystallized fructose remains inthe storage containers. Thereafter, the flavors, sodium saccharin, andcolor solutions are added to match the flavor and color of the desiredend product. The mixture is agitated until homogeneous. The finalproduct is clear and has a vanilla (butterscotch) citrus flavor andodor. It is free of particles of suspended matter.

It has been determined that the objectionable bitter aftertastes foundin liquid preparations including these active pharmaceutical agents havevirtually been eliminated in the unique compositions employing thecombination of flavor masking agents of this invention. Taste testingresults have been highly positive in terms of overall taste, mouth feel,and sweetness, as well as the absence of unpleasant aftertastes.

Women have reported that this composition has provided satisfactoryresults in relieving a wide range of premenstrual and menstrualdiscomforts. Women report the liquid is easy to swallow and relief fromdiscomforts is fast and complete. Daytime use of the composition affordsthe user highly satisfactory results in relief of PMS and menstrualdiscomforts. The benefits of the composition are seen as particularlyimportant at bedtime, when unrelieved premenstrual and menstrualdiscomfort may make a good night's sleep impossible.

EXAMPLE II

A liquid mixture is prepared essentially according to the method ofExample I, having the following composition.

    ______________________________________                                        Component     Label Claim Overage  Gms/Liter                                  ______________________________________                                        (1) ethyl alcohol 95%,                                                                          12.5% v/v   2%     115.0                                        USP           (100% ethanol)                                                  propyleneglycol,                 72.5                                         USP                                                                           acetaminophen,                                                                              500 mgs/fl. oz                                                                            2%     17.3                                         USP                                                                           benzoic add                      2.0                                      (2) demin. water                     102.4                                        pyrilamine maleate,                                                                          25 mgs/fl. oz                                                                            2%     0.90                                         USP                                                                           citric acid, anh,                1.00                                         USP                                                                       (3) demin. water                     102.4                                        pamabrom       50 mgs/fl. oz                                                                            2%     1.73                                     (4) high fructose corn               726.65                                       syrup (sp. gr. 1.321)                                                     (5) flavors:                                                                      natural and artificial           0.90                                         orange orange                                                                 natural and artificial           1.00                                         lemon                                                                         natural and artificial           0.70                                         mint                                                                          natural and artificial           2.80                                         cherry                                                                        sodium saccharin                 1.50                                     (6) color solutions                                                                             q.s.               1.75                                                                          1,150.53                                 ______________________________________                                    

EXAMPLE III

A liquid mixture is prepared essentially according to the method ofExample I, having the following composition.

    ______________________________________                                        Component     Label Claim Overage  Gms/Liter                                  ______________________________________                                        (1) ethyl alcohol 95%,                                                                          6.25% v/v   2%     57.5                                         USP           (100% ethanol)                                                  propyleneglycol,                 70.0                                         USP                                                                           acetaminophen,                                                                              750 mgs/fl. oz                                                                            2%     26.0                                         USP                                                                           benzoic acid                     2.0                                      (2) demin. water                     102.4                                        pyrilamine maleate,                                                                          30 mgs/fl. oz                                                                            2%     1.04                                         USP                                                                           citric acid, anh,                1.50                                         USP                                                                       (3) demin. water                     102.4                                        pamabrom       50 mgs/fl. oz                                                                            2%     1.73                                     (4) high fructose corn               693.68                                       syrup (sp. gr. 1.321)                                                     (5) flavors:                                                                      natural and artificial           1.05                                         orange                                                                        natural and artificial           0.80                                         lemon                                                                         natural and artificial           0.70                                         mint                                                                          natural and artificial           2.55                                         chocolate                                                                     sodium saccharin                 1.50                                     (6) color solutions                                                                             q.s.               1.75                                                                          1,137.1                                  ______________________________________                                    

While the foregoing examples are directed to compositions for the reliefof premenstrual and menstrual discomforts, the novel combination offlavorings can be used with any of the active ingredients alone or incombination.

Also, the sweetening and bodying agent, high fructose corn syrup, may bereplaced by sucrose or invert sugar syrup, with or without the additionof 70% sorbitol solutions.

We claim:
 1. A liquid composition comprising:(i) at least one active pharmaceutical agent including at least one and at most two types of agents which are selected from the group consisting of the following types of agents: analgesics, antihistamines, and diuretics; each active pharmaceutical agent being present in an effective amount with at least one from the group being unpleasant in taste, and each being dissolved in a liquid vehicle; (ii) 5-25 percent by volume alcohol; and (iii) an active flavor enhancing composition selected from the group consisting of (a) citrus and mint ingredients, (b) vanilla and mint ingredients, and (c) citrus, vanilla and mint ingredients; said active flavor enhancing composition being present in an amount sufficient to mask the unpleasant taste of any such active pharmaceutical agent present in the liquid composition.
 2. A liquid composition as recited in claim 1, wherein the active pharmaceutical agent is selected from the group consisting of ibuprofen, acetaminophen, pyrilamine maleate, diphenhydramine and pamabrom.
 3. A liquid composition as recited in claim 1, wherein the liquid composition contains at least 30% sucrose and sorbitol syrup.
 4. A liquid composition as recited in claim 1, wherein the liquid composition contains 15-25 percent alcohol.
 5. A liquid composition as recited in claim 1, wherein the active flavor enhancing composition is selected from the group consisting of (a) citrus and mint ingredients, and (b) vanilla and mint ingredients; the mint ingredient being present in an amount less than that representing the taste threshold for mint; and the active pharmaceutical agent is ibuprofen.
 6. A liquid composition as recited in claim 1, wherein the liquid composition contains at least 30 percent corn syrup.
 7. A liquid composition as recited in claim 1, wherein any active pharmaceutical agent present consists essentially only of one or two active pharmaceutical agents selected from the group consisting of analgesics, antihistamines, and diuretics.
 8. A liquid composition as recited in claim 7, wherein the active flavor enhancing composition consists essentially of (a) citrus and mint ingredients, or (b) vanilla and mint ingredients.
 9. A liquid composition comprising:(i) at least one active pharmaceutical agent selected from the group consisting of analgesic, antihistamine and diuretic; wherein the analgesic is selected from the group consisting of acetaminophen and ibuprofen, and the antihistamine is selected from the group consisting of pyrilamine maleate and diphenhydramine; said active pharmaceutical agent being present in an effective amount, unpleasant in taste, and dissolved in a liquid vehicle; (ii) 12-25 percent by volume of alcohol; (iii) at least 30 percent by volume of corn syrup; and (iv) an active flavor enhancing composition selected from the group consisting of (a) citrus and mint ingredients, (b) vanilla and mint ingredients, and (c) citrus, vanilla and mint ingredients; said active flavor enhancing composition being present in an amount sufficient to mask the unpleasant taste of the active pharmaceutical agent.
 10. A liquid composition as recited in claim 9, wherein the active pharmaceutical agent is ibuprofen.
 11. The liquid composition of claim 9, wherein the diuretic is pamabrom.
 12. A liquid composition comprising:(i) at least one active pharmaceutical agent selected from the group consisting of analgesics, antihistamines, diuretics, and mixtures thereof, each said active pharmaceutical agent being present in an effective amount with at least one being unpleasant in taste, and each being dissolved in a liquid vehicle; (ii) 5-25 percent by volume alcohol; and (iii) an active flavor enhancing composition including as ingredients at least mint and also only one selected from the group consisting of citrus and vanilla; said active flavor enhancing composition being present in an amount sufficient to mask the unpleasant taste of any such active pharmaceutical agent present in the liquid composition.
 13. A liquid composition as recited in claim 12, wherein at least one of the active pharmaceutical agents present is selected from the group consisting of ibuprofen, acetaminophen, pyrilamine maleate, diphenhydramine and pamabrom.
 14. A liquid composition as recited in claim 12, wherein the liquid composition contains at least 30 percent corn syrup.
 15. A liquid composition as recited in claim 12, wherein the liquid composition contains at least 30% sucrose and sorbitol syrup.
 16. A liquid composition as recited in claim 12, wherein the liquid composition contains 15-25 percent alcohol.
 17. A liquid composition as recited in claim 12, wherein the mint ingredient is present in an amount less than that representing the taste threshold for mint, and the active pharmaceutical agent is ibuprofen.
 18. A liquid composition as recited in claim 12, wherein any active pharmaceutical agent present consists essentially only of one or two active pharmaceutical agents selected from the group consisting of analgesics, antihistamines, and diuretics.
 19. A liquid composition as recited in claim 18, wherein the active flavor enhancing composition consists essentially of (a) citrus and mint ingredients, or (b) vanilla and mint ingredients. 